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Family-based association of FKBP5 in bipolar disorder

Molecular Psychiatry volume 14, pages 261–268 (2009)Cite this article

Abstract

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic–pituitary–adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.

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Acknowledgements

This work was supported by grants from the National Institute of Mental Health (R01 MH-042243 and R01 MH-061613), the Charles A Dana Foundation Consortium on the Genetic Basis of Manic Depressive Illness, the National Alliance for Research on Schizophrenia and Depression, the Alex Brown Foundation and the Stanley Medical Research Institute. Dr Willour and Dr Potash were also supported by Margaret Ann Price Investigatorships. Some DNA samples were prepared and distributed by Rutgers University under a contract from the NIMH. We are grateful to Yuqing Huo, Kuangyi Miao and Brandie Craighead for their contributions. We are also grateful to the many interviewers and diagnosticians who contributed to this project, and to the families who devoted their time and effort to the study.

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Author notes

  1. V L Willour and H Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA

    V L Willour, J Toolan, P Belmonte, F S Goes, R S Lee, D F MacKinnon, F M Mondimore, B Schweizer, J R DePaulo Jr & J B Potash

  2. Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI, USA

    H Chen

  3. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    D J Cutler

  4. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    P P Zandi

  5. Department of Psychiatry, University of Chicago, Chicago, IL, USA

    E S Gershon

  6. US Department of Health and Human Services, Genetic Basis of Mood and Anxiety Disorders Unit, Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    F J McMahon

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Bipolar Disorder Phenome Group, NIMH Genetics Initiative Bipolar Disorder Consortium

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Correspondence to V L Willour.

Additional information

The Bipolar Disorder Phenome Group consists of Francis McMahon, Jo Steele, Justin Pearl, Layla Kassem, Victor Lopez from the Genetic Basis of Mood and Anxiety Disorders Unit, Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD; James Potash, Dean MacKinnon, Erin Miller, Jennifer Toolan from the Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD; Peter Zandi from the Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Thomas Schulze from the Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany; Evaristus Nwulia from the Department of Psychiatry, Howard University Hospital, Washington, DC; Sylvia Simpson from the Department of Psychiatry, University of Colorado at Denver, Denver, CO.

Some of the data and biomaterials were collected in four projects that participated in the NIMH Bipolar Disorder Genetics Initiative from 1991–1998. The Principal Investigators and Co-Investigators were Indiana University, Indianapolis, IN, U01 MH46282, John Nurnberger, MD, PhD, Marvin Miller, MD and Elizabeth Bowman, MD; Washington University, St Louis, MO, U01 MH46280, Theodore Reich, MD, Allison Goate, PhD and John Rice, PhD; Johns Hopkins University, Baltimore, MD U01 MH46274, J Raymond DePaulo, Jr, MD, Sylvia Simpson, MD, MPH and Colin Stine, PhD; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD, Elliot Gershon, MD, Diane Kazuba, BA and Elizabeth Maxwell, MSW. Other data and biomaterials were collected in 10 NIMH Bipolar Disorder Genetics Initiative projects from 1999–2003. The Principal Investigators and Co-Investigators were Indiana University, Indianapolis, IN, R01 MH59545, John Nurnberger, MD, PhD, Marvin J Miller, MD, Elizabeth S Bowman, MD, N Leela Rau, MD, P Ryan Moe, MD, Nalini Samavedy, MD, Rif El-Mallakh, MD (at University of Louisville), Husseini Manji, MD (at Wayne State University), Debra A Glitz, MD (at Wayne State University), Eric T Meyer, MS, Carrie Smiley, RN, Tatiana Foroud, PhD, Leah Flury, MS, Danielle M Dick, PhD, Howard Edenberg, PhD; Washington University, St Louis, MO, R01 MH059534, John Rice, PhD, Theodore Reich, MD, Allison Goate, PhD, Laura Bierut, MD; Johns Hopkins University, Baltimore, MD, R01 MH59533, Melvin McInnis MD, J. Raymond DePaulo, Jr, MD, Dean F MacKinnon, MD, Francis M Mondimore, MD, James B Potash, MD, Peter P Zandi, PhD, Dimitrios Avramopoulos, PhD and Jennifer Payne, MD; University of Pennsylvania, PA, R01 MH59553, Wade Berrettini MD, PhD; University of California at Irvine, CA, R01 MH60068, William Byerley MD and Mark Vawter MD; University of Iowa, IA, R01 MH059548, William Coryell MD and Raymond Crowe MD; University of Chicago, IL, R01 MH59535, Elliot Gershon, MD, Judith Badner PhD, Francis McMahon MD, Chunyu Liu PhD, Alan Sanders MD, Maria Caserta, Steven Dinwiddie MD, Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567, John Kelsoe, MD, Rebecca McKinney, BA; Rush University, IL, R01 MH059556, William Scheftner MD, Howard M Kravitz, DO, MPH, Diana Marta, BS, Annette Vaughn-Brown, MSN, RN and Laurie Bederow, MA; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, Francis J McMahon, MD, Layla Kassem, PsyD, Sevilla Detera-Wadleigh, PhD, Lisa Austin, PhD, Dennis L Murphy, MD.

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Willour, V., Chen, H., Toolan, J. et al. Family-based association of FKBP5 in bipolar disorder. Mol Psychiatry 14, 261–268 (2009). https://doi.org/10.1038/sj.mp.4002141

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